Considerable research has been conducted in the use of perfluorinated compounds as oxygen and CO.sub.2 carriers in so-called "artificial blood" or blood substitutes. A comprehensive survey of the state of the art was published by Riess, J. G. et al. in Angewandte Chemie, International Edition in English, Vol. 17, pages 621-634 (September, 1978), which includes an extensive bibliography of prior publications. While the ability of perfluorinated compounds to function as blood substitutes has been conclusively demonstrated, search for the ideal compound or compounds best suited for the various situations in which blood substitutes can be employed is continuing. Research in the area of blood substitutes has been hampered, however, by the lack of commercial availability of prospective inert fluorocarbons.
Most of the previous investigations have been carried out with three commercially available perfluoro compounds:
(I) a product of the 3M Company designated FX-80, a mixture of fluorinated products including perfluoro 2-butyl tetrahydrofuran;
(II) Perfluorotributyl amine
(III) Perfluorodecalin.
To quality as a component of blood substitute compositions, a fluorocarbon candidate compound must possess the following properties:
(a) inertness
(b) emulsifiability
(c) intermediate vapor pressure
(d) be nonaccumulative in tissues.
The pure fluorocarbon can not be used as such as a blood substitute because it will not dissolve salts, proteins and other biological materials. The fluorocarbon compound, accordingly, is emulsified in water with the aid of certain emulsifying agents. Stability of the emulsion on storage and in vivo are necessary criteria to be met by a successful blood substitute. While the compounds (I) and (II) identified above form stable emulsions, compound (III) does not.
The ideal candidate must also exhibit an intermediate vapor pressure at biological temperatures. The fluorocarbon should be slowly expirated from the body as natural blood is being regenerated. While this is facilitated with compounds of higher vapor pressure, unfortunately, excessively high vapor pressure, as is the case with compound (I), results in pulmonary edema, rendering such compounds undesirable.
The desired fluorocarbon compound should be one that does not accumulate in body organs after it is removed from the blood. Thus, while compound (II) forms stable emulsions, it is not deemed suitable as a viable candidate for a blood substitute because it is retained by the liver.
One theory that has been advanced to explain the observations cited above attributes the emulsifiability of compounds (I) and (II) to the presence of the heteroatom therein. Compound (III) has no heteroatom and is therefore not capable of forming a stable emulsion. However, the same factor which influences emulsification has also been blamed for causing retention of the compounds in various body organs. An alternative theory attributes fluorocarbon retention to the relative vapor pressure of the compounds, and correlations have been developed which demonstrate that compounds with higher vapor pressure have faster expiratory excretion.
A better understanding of the mechanism of fluorocarbon retention would enable the synthesis of fluorocarbons possessing all the properties required for an artificial blood substitute. Accordingly, under contracted sponsorship by the National Heart and Lung Institute of the Public Health Service, HEW, a project was undertaken by Harvard University and Air Products and Chemicals, Inc. for the synthesis of a wide variety of heteroatomic fluorocarbons by electrochemical fluorination and the screening of these compounds in synthetic blood preparations. Preparation of emulsions of these synthesized fluorocarbons and their testing in vivo would be useful in differentiating the postulated mechanisms of fluorocarbon retention.
In carrying out the synthesis of the program, 17 organic compounds, falling in 8 chemical classes, were electrochemically fluorinated, resulting in 24 samples submitted for biological evalulation. Only two of the compounds prepared in this program showed promise as oxygen transport media in blood substitute compositions, warranting further extensive evaluation; one of these being the compound claimed in the present patent application.
The electrofluorination of various organic compounds is described in U.S. Pat. No. 2,616,927. Included among the compounds of this patent is the electrofluorination of aromatic amines to the corresponding cyclic fluorinated amines. For example, N,N-dimethyl aniline is converted to perfluoro-N,N-dimethyl cyclohexylamine. Relying on this disclosure, it was attempted in the experimental program leading to the present invention, to produce perfluorodicyclohexyl ether by electrofluorination of diphenyl ether. The electrolysis proceeded only with difficulty and at low current density. Examination of the reactor contents at the conclusion of the run showed that a large amount of polymeric partially fluorinated solid was produced.
The fluorination of aromatic amines to the corresponding perfluorocyclohexyl amines is also described in U.S. Pat. No. 2,616,927. An attempt to produce perfluoro-N,N-dibutyl cyclohexyl amine by electrofluorination of dibutyl aniline proved unsuccessful. Since cell fouling is especially pronounced with aromatic substrates, a small amount of ethyl thioacetate was included during the electrofluorination of the dibutyl aniline. Despite this reported remedy to prevent fouling (per U.S. Pat. Nos. 3,028,321 and 3,692,643), the electrofluorination proceeded only with difficulty at low current densities and no liquid fluorocarbon layer was found at the end of the run.
In like manner, in the initial attempt to fluorinate dimethyl aniline, no liquid fluorocarbon product was obtained. With a second charge of the dimethyl aniline some fluorocarbon was obtained but GC analysis indicated that the product was a complex mixture which was not alkali stable, the main component decreasing in concentration during the standard alkali work-up procedure employed in the attempted purification of the crude cell product. Accordingly, no further attempt was made to produce perfluorinated cyclohexyl amines by electrofluorination of aromatic amines.
The results of electrical fluorination of N,N-dimethyl aniline and N,N-dimethyl cyclohexyl amine are reported by Plashkin, V.S. et al, J. Org. Chem (USSR) Vol. 6, pp 1010-1014 (1970). The electrofluorination of these compounds as reported was accompanied by cleavage of the carbon-carbon bond giving rise to the accompanying production of perfluoro-N,N-dimethyl-n-hexyl amine.
The prior literature on perfluorinated compounds as oxygen carriers in compositions intended as blood substitutes is extensively reviewed in the above-cited paper by Riess et al and the cited bibliography. Proposed blood substitute compositions containing emulsified perfluorocarbon compounds are also described in U.S. Pat. Nos. 3,962,439 and 3,989,843. Among the compounds therein disclosed as oxygen transfer compounds are: perfluoroalkyl cyclohexanes having 3 to 5 carbon atoms in the alkyl group, perfluoro diethylcyclohexylamine and perfluorinated alkylamines. According to U.S. Pat. No. 3,962,439, it is important that the emulsions of the fluorocarbon compounds be substantially free of particles above 0.4 microns and preferably the emulsion should consist of particles below 0.3 microns, particularly when these are intended for use by injection in mammals as a blood substitute.